1p/19q co-deletion status is associated with distinct tumor-associated macrophage infiltration in IDH mutated lower-grade gliomas.,Cellular Oncology

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1p/19q co-deletion status is associated with distinct tumor-associated macrophage infiltration in IDH mutated lower-grade gliomas.
Cellular Oncology ( IF 6.6 ) Pub Date : 2020-09-11 , DOI: 10.1007/s13402-020-00561-1
Yanyu Zhang _{1,

2} , Yuan Xie ₁ , Liqun He _{3,

4} , Jiefu Tang ₅ , Qiyuan He ₁ , Qingze Cao ₁ , Langjun Cui ₁ , Wei Guo ₆ , Kai Hua ₇ , Anna Dimberg ₄ , Liang Wang ₆ , Lei Zhang _{1,

5}

Affiliation

Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China.
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 582, BMC, Husargatan 3, 75123, Uppsala, Sweden.
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neuro-injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China.
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, 75185, Uppsala, Sweden.
Department of Spine Surgery, Huaihua No.2 Hospital, Hunan University of Medicine, Huaihua, 418000, China.
Department of Neurosurgery, Tangdu Hospital, Air Force Medical University of PLA (the Fourth Military Medical University), 569 Xinsi Road, Xi'an, 710038, China.
The College of Life Sciences, Northwest University, Xi'an, 710069, China.

Background

Tumor-associated macrophages (TAM)s are critical regulators of glioma progression. As yet, however, TAMs in isocitrate dehydrogenase (IDH) mutated lower-grade gliomas (LGGs) have not been thoroughly investigated. The aim of this study was to determine whether 1p/19q co-deletion status affects the TAM phenotype or its prevalence in IDH mutated LGGs.

Methods

TAMs in IDH mutated LGGs were analyzed using transcriptome data from 230 samples in the TCGA database in combination with transcriptome data from single-cell RNA sequencing of IDH-mutated LGGs. Proteins potentially involved in TAM regulation were examined by immuno-staining in primary LGG samples harboring IDH mutations. Essential signaling pathways regulating TAM phenotypes were investigated in a glioma mouse model using small molecule inhibitors.

Results

Most of the TAMs in IDH-mutated LGGs expressed the M1 activation markers CD86 and TNF, whereas a subset of individual TAMs co-expressed both M1 and M2-related markers. Bioinformatics analysis in combination with immuno-staining of IDH-mutated patient samples revealed higher amounts of TAMs expressing M2-related markers in 1p/19q non-codeletion IDH-mutated LGGs compared to 1p/19q codeletion LGGs. The levels of transforming growth factor beta 1 (TGFβ1) and macrophage colony-stimulating factor (M-CSF) were significantly higher in 1p/19q non-codeletion LGGs than in 1p/19q codeletion LGGs. M-CSF and TGFβ1 signal inhibition decreased tumor growth and modulated the TAM phenotype in a glioma mouse model.

Conclusions

Our data indicate that 1p/19q co-deletion status relates to distinct TAM infiltration in gliomas, which is likely mediated by M-CSF and TGFβ1 signaling. M-CSF and TGFβ1 signaling may play a pivotal role in regulating the TAM phenotype in glioma.

中文翻译：

1p / 19q共缺失状态与IDH突变的低级神经胶质瘤中明显的肿瘤相关巨噬细胞浸润有关。

背景

肿瘤相关巨噬细胞（TAM）是神经胶质瘤进展的关键调节器。但是，到目前为止，尚未对异柠檬酸脱氢酶（IDH）突变的低级神经胶质瘤（LGG）中的TAM进行彻底研究。这项研究的目的是确定1p / 19q共缺失状态是否会影响TAM表型或其在IDH突变的LGG中的患病率。

方法

使用TCGA数据库中230个样品的转录组数据，结合IDH突变LGG的单细胞RNA测序的转录组数据，分析IDH突变LGG中的TAM。通过对带有IDH突变的原LGG样品进行免疫染色，检查了可能参与TAM调控的蛋白质。使用小分子抑制剂在胶质瘤小鼠模型中研究了调节TAM表型的基本信号通路。

结果

IDH突变的LGG中的大多数TAM均表达M1激活标记CD86和TNF，而单个TAM的子集共表达M1和M2相关标记。生物信息学分析与IDH突变患者样品的免疫染色相结合，发现与1p / 19q突变LGG相比，在1p / 19q非代码突变IDH突变的LGG中表达M2相关标记的TAM数量更高。在1p / 19q非编码LGG中，转化生长因子β1（TGFβ1）和巨噬细胞集落刺激因子（M-CSF）的水平显着高于1p / 19q非编码LGG。在神经胶质瘤小鼠模型中，M-CSF和TGFβ1信号抑制降低了肿瘤的生长并调节了TAM表型。